Efficacy and Safety of Ivermectin 1% Cream in Treatment of Papulopustular Rosacea: Results of Two Randomized, Double-Blind, Vehicle-Controlled Pivotal Studies

March 2014 | Volume 13 | Issue 3 | Original Article | 316 | Copyright © March 2014

Linda Stein Gold MD,a Leon Kircik MD,b Joseph Fowler MD,c Jerry Tan MD,d Zoe Draelos MD,e Alan
Fleischer MD,f Melanie Appell MD,g Martin Steinhoff MD,h Charles Lynde MD,i
Hong Liu MSc,j and Jean Jacovella MDk
on behalf of the Ivermectin Phase III Study Group

aHenry Ford Medical Center, Department of Dermatology, Detroit, MI
bDerm Research, PLLC, Louisville, KY
cDermatology Specialists Research, Louisville, KY
dWindsor Clinical Research, Inc., Windsor, ON, Canada
eDepartment of Dermatology, Duke University School of Medicine, Durham, NC
fDepartment of Dermatology, Wake Forest University Health Sciences, Winston, Salem, NC
gTotal Skin and Beauty Dermatology Center, PC, Birmingham, AL
hUniversity of California-San Francisco, San Francisco, CA
iLynderm Research, Inc., Markham, ON, Canada
jGalderma R&D, Cranbury, NJ
kGalderma R&D, Sophia Antipolis, France

Abstract
BACKGROUND: Treatments for papulopustular rosacea (PPR) are limited.
OBJECTIVE: To demonstrate the efficacy and safety of once-daily ivermectin 1% cream in subjects with moderate to severe PPR.
METHODS: Two identically designed, randomized, double-blind, controlled studies of ivermectin 1% cream (IVM 1%) or vehicle once daily for 12 weeks were conducted in subjects with moderate to severe PPR. Efficacy assessments were Investigator's Global Assessment (IGA) of disease severity and inflammatory lesion counts. Safety assessments included incidence of adverse events (AEs) and local tolerance parameters. Subjects evaluated their rosacea and completed satisfaction and quality of life (QoL) questionnaires.
RESULTS: In both studies, a greater proportion of subjects in the IVM 1% group achieved treatment success (IGA “clear” or “almost clear”): 38.4% and 40.1% vs 11.6% and 18.8% for vehicle (both P<.001), respectively. Ivermectin was superior to vehicle in terms of reduction from baseline in inflammatory lesion counts (76.0% and 75.0% vs 50.0% for both vehicle groups, respectively). For all endpoints, starting at week 4 and continuing through week 12, IVM 1% was statistically significantly superior (P<.001). Fewer subjects treated by IVM 1% reported dermatologic AEs, and a higher proportion of subjects were observed to have no skin dryness or itching compared to vehicle. Significantly more subjects receiving IVM 1% reported having an “excellent” or “good” improvement, along with an improved QoL.
CONCLUSION: Ivermectin 1% cream was effective and safe in treating inflammatory lesions of papulopustular rosacea.

J Drugs Dermatol. 2014;13(3):316-323.

INTRODUCTION

Papulopustular rosacea (PPR) is a chronic inflammatory disorder characterized by facial papules, pustules, and persistent erythema.1 It is highly prevalent and associated with adverse impact on quality of life and depression.2 The etiology of rosacea is multifactorial. In addition to neurovascular dysregulation, the facial skin of patients with rosacea is affected by augmented proinflammatory immune responses.3 The principal active cathelicidin peptide (LL-37) is highly concentrated in skin affected by rosacea and can contribute to acute inflammation.4 Moreover, PPR is characterized by the presence of inflammatory infiltrates that accompany flares, along with a heightened immune response involving neutrophilic infiltration and increased gene expression of IL-8.5 In addition to exogenous factors (including UV light, heat, and alcohol), it may be triggered by Demodex folliculorum mites.3 Some studies of PPR observed higher mite densities compared to controls.6-7 Therefore, a multitude of factors can activate neurovascular and/or immune responses, and consequential inflammation leading to flares of rosacea.3
Only a few therapeutic alternatives currently exist in the treatment of PPR. In the United States, only three FDA-approved